Primary Sjogren's syndrome (pSS) is a common, progressive autoimmune disorder distinguished by immunological targeting of salivary and lacrimal glands. Systemic manifestations are variable and may include vasculitis, neurologic disease, interstitial nephritis, thyroid dysfunction, fatigue, arthritis, and lymphoma. A concurrent second autoimmune disease, such as systemic lupus erythematosus or rheumatoid arthritis, occurs in half of all SS patients. Heterogeneity of clinical and laboratory findings are influenced by underlying genetic variation that remains largely unexplored. Diagnosis is often delayed and problematic and therapies are primarily directed at symptoms. Our overall goal is to understand the etiology and pathogenesis of SS through genetics. We will evaluate selected interferon (INF) pathway candidate genes and apply unbiased genome scan approaches to a carefully defined sub-phenotype of SS in large patient cohorts to define genetic variation that leads to the INF dependence of SS. Our preliminary studies have shown interferon (IFN) mediated pathways are dysregulated in SS and appear to be predominant in the subset of patients with anti-Ro/SSA. We propose to apply state-of-the art genetic and genomic approaches to identify and characterize molecular disease mechanisms in this subset of SS patients. We will first generate global gene expression data in our cohort of SS patients to identify those with dysregulation of IFN pathways. We will also measure serum IFNa activity through cellular functional assays. Homogeneous subsets of patients with these two IFN-related traits, plus anti-Ro/SSA will then be selected for genome wide association studies tailored to identify and characterize important variants involved in dysregulation of IFN pathways in SS. Replication, fine mapping and characterization of genetic effects will be pursued. These studies should reveal novel, fundamental knowledge about SS that will lead to the development of more precise diagnostic tests and therapeutic intervention targeted at causal molecular events.